The following are key points to remember from this review about current approaches to the diagnosis and treatment of cardiac amyloidosis:

The most common forms of amyloid that affect the heart are immunoglobulin-derived light chains and transthyretin (TTR, previously called prealbumin). There is a slight male predominance of AL (light-chain) cardiac amyloidosis, and the disease generally presents from the fifth to seventh decade, although it may occur at all ages from the fourth decade onward. The median survival from onset of heart failure (HF) is about 6 months in untreated patients, but therapies can put the disease into a prolonged remission and extend life by many years.

It is estimated that AL amyloidosis is approximately one-tenth as common as multiple myeloma, with an estimated annual age-adjusted incidence in the United States of 10.5 cases per million person-years. Approximately 5-10% of patients with AL amyloidosis will have evidence of overt multiple myeloma, and a similar proportion of multiple myeloma patients will have AL amyloidosis. In myeloma, amyloid infiltration of the heart is required before light-chain cardiotoxicity can be clinically manifest.

AL amyloidosis, is a multi-organ disorder wherein renal, neural, and/or dermatologic involvement often coexists with heart involvement. It most commonly affects the kidney, resulting in nephrotic syndrome, with clinical cardiac involvement being the second most common presenting manifestation. Less commonly, symptomatic hepatic and gastrointestinal infiltration may occur. Other organ systems that may be involved include the peripheral and autonomic nervous system, the vasculature, and the soft tissues. Cerebral involvement does not occur in AL amyloidosis.

The severity of HF in AL amyloidosis was more severe than in TTR amyloidosis, despite greater left ventricular (LV) mass in the latter—the authors provide evidence suggesting that amyloid fibrils may have both toxic and infiltrative components.

The most common early manifestation of cardiac amyloidosis of any type is exertional dyspnea on exertion (which is due to LV diastolic dysfunction), which progresses relatively rapidly, and is often followed by peripheral edema and ascites. Peripheral edema in AL amyloidosis may also be due to hypoalbuminemia associated with amyloid-related nephrotic syndrome, and proteinuria should always be sought. However, the atria, although they do dilate, are also abnormally stiff, and prominent V waves may be seen in the pulmonary capillary wedge tracings in the absence of significant mitral regurgitation, and likely contribute to dyspnea on exertion. Atrial arrhythmia may be the initial manifestation of the disease; surprisingly, this is relatively uncommon as a presenting feature, particularly in AL amyloidosis. Exertional syncope, most likely due to a low and fixed cardiac output, can occur, and this has a particularly poor prognosis.

Thromboembolism may thus be an early manifestation of the disease, and unless the clinician is aware of the phenomenon of left atrial systolic dysfunction, the source of neurological or systemic embolism may not be recognized.

The signs of the noncardiac disease are commonly present. Approximately 10% of patients have macroglossia, which may vary from very obvious tongue enlargement to subtle tooth indentation of the tongue. Periorbital bruising in the setting of HF is almost pathognomonic of light-chain amyloidosis; as it may be subtle, the eyelids should be inspected for small bruises. Hepatomegaly usually reflects congestion, but an enlarged liver may also be due to amyloid infiltration in patients with AL amyloidosis.

Unlike severe HF caused by most other etiologies, a third heart sound is uncommon in cardiac amyloidosis, as is a fourth heart sound. Valvular dysfunction due to amyloidosis is rarely severe, other than, on occasion, tricuspid regurgitation.

Electrocardiography (ECG) typically shows low-voltage QRS complexes, but the P-wave is usually of normal voltage, but frequently abnormal in morphology, and is often markedly prolonged, representing slowed atrial conduction due to amyloid infiltration. Low-voltage ECG often precedes HF, and may be present before an increase in LV wall thickness is apparent on echocardiogram. This is an early marker of the disease. Low-voltage QRS complexes are far less common in ATTR than in AL amyloidosis, despite a greater amyloid burden in the heart.

The echocardiogram typically shows concentric LV thickening, often with right ventricular (RV) thickening. The LV wall may be more echogenic than in true LV hypertrophy, and, due to the extensive amyloid deposits, LV wall thickness frequently equals or exceeds 15 mm. A wall thickness >18 mm can be seen in AL amyloidosis, but is more common in ATTR. It is unusual for hypertensive heart disease to have LV walls >15 mm, unless hypertension is severe, longstanding, and persistent, and the discrepancy between increased LV mass on echocardiogram and low voltage on ECG should increase suspicion of cardiac amyloidosis. There may be both loss of reservoir function (absence of atrial expansion during ventricular systole) and loss of contractile function (absence of atrial contraction during late ventricular diastole).

Cardiac magnetic resonance (CMR) imaging shows two main features. These include the difficulty in nulling the myocardium following gadolinium injection and a noncoronary, usually subendocardial, pattern of delayed gadolinium enhancement, both within the ventricular myocardium and in the atrium.

The sine qua non of diagnosis, in patients with evidence of monoclonal gammopathy, is tissue biopsy showing amyloid deposits.

Therapy of AL cardiac amyloidosis is two-fold: optimal treatment of HF and chemotherapy aimed at abolishing the amyloidogenic plasma cell dyscrasia. Diuretic agents (a loop diuretic with spironolactone) are the mainstay of HF therapy, as angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are poorly tolerated due to hypotension. Beta-blockers may also aggravate hypotension and are usually avoided (they may be used cautiously in selected patients with atrial fibrillation and a rapid ventricular response). Calcium-channel blockers often significantly worsen congestive HF. Digoxin appears to offer no benefit in HF due to amyloid cardiomyopathy, and digoxin toxicity with “therapeutic digoxin levels” may occur because of altered binding properties.

Even when the patient is in sinus rhythm, anticoagulation should be administered if the echocardiogram shows features of left atrial mechanical dysfunction, as thrombus formation and thromboembolism may occur in these patients.

In the authors' experience, amiodarone and dofetilide are well tolerated for atrial arrhythmias. Nonsustained ventricular arrhythmias are uncommon in such patients and sudden death, if it occurs, is most commonly due to sudden profound bradycardia or pulseless electrical activity. There is no proven benefit of either prophylactic pacing or prophylactic implantable defibrillator in these patients.

Proteosome-inhibiting agents, specifically bortezomib, have considerably improved the prognosis of patients with AL cardiac amyloidosis. Bortezomib is relatively well-tolerated, even in the presence of amyloid cardiomyopathy, and is usually combined with dexamethasone, frequently with low-dose cyclophosphamide.

High-dose chemotherapy with autologous stem-cell transplantation is generally reserved for suitable cardiac amyloidosis patients who have failed to fully respond to oral regimens, and may produce a complete hematologic response. Stem cell collection is often associated with fluid retention and hypotension, and atrial arrhythmias may occur following chemotherapy. Generally, hypotension is well-tolerated, and the temptation to treat with intravenous fluids should be avoided in the asymptomatic patient.

Cardiac transplantation in AL amyloidosis has been performed, but the outcome depends on extremely careful selection of patients. One-year overall survival was 64% after LV assist device (LVAD) implantation, with no difference between amyloidosis and non-amyloidosis patients, but with a very poor survival if the LV end-diastolic dimension was <46 mm.

A promising therapeutic option appears to be a two-pronged approach of depletion of circulating Serum amyloid P component (SAP) followed by the administration of a fully humanized immunoglobulin-1 anti-SAP monoclonal antibody to target the SAP on the amyloid fibrils.